Blood coagulation is the result of coordinated activation of various plasma proteases, their co-factors, and platelets. This cascade reaction is divided into the intrinsic (contact activation) pathway, the extrinsic (tissue factor activation) pathway, and the common pathway (prothrombin and thrombin generation) pathway (Gailani and Renne, 2007, Arterioscler Thromb Vasc Biol, 27, 2507-2513; Gailani and Renne, 2007, J Thromb Haemost, 5, 1106-1112; Mackman, Tilley et al., 2007, Arterioscler Thromb Vasc Biol, 27, 1687-1693). In the blood coagulation process, the most important physiological activator is tissue factor. Under physiological conditions, tissue factor is expressed on the vessel wall, while under pathological conditions tissue factor is expressed in circulating monocytes and microparticles. The tissue factor-factor VIIa complex catalyzes the formation of factor Xa, and factor Xa in turn cleaves prothrombin to produce thrombin. In the intrinsic blood-coagulation pathway, factor XIa is catalytically produced by contact with activator XIIa, which in turn leads to the activation of factor IX and factor X. Factor XIa is only involved in the intrinsic pathway. In the absence of an injury, abnormal thrombosis at the base of the vessel wall is achieved by the intrinsic pathway. In addition, thrombin and the tissue factor-factor VIIa complex can also activate intrinsic coagulation proteases, resulting in pathways closely related to blood-coagulation. Blood-coagulation and activation of platelets lead to thrombosis and hemostasis, and are regulated by local plasmin (Schumacher, Luettgen et al., 2010, Arterioscler Thromb Vasc Biol, 30, 388-392).
Hemostasis is an advantageous process for the maintenance of the liquid state of blood and protection of the integrity of blood vessels. Thrombosis is a disadvantageous process that causes blood vessel occlusion, and is the major cause of cardiovascular morbidity and mortality. Currently there are many drugs for treatment of thromboembolism, including anticoagulants (such as heparin and warfarin), fibrinolytic agents (such as streptokinase and urokinase), and platelet inhibitors (such as aspirin) as commonly used in clinical settings. However, these antithrombotic drugs for treatment of cardiovascular diseases have the drug-related side effect—bleeding. For example, heparin as an antithrombotic agent has a highly variable dose-dependent response, and its anticoagulation action must be closely monitored to avoid the risk of severe bleeding. The platelet inhibitor aspirin given at high doses will cause the risk of gastrointestinal bleeding. This necessitates selecting a molecular target to distinguish between hemostasis and thrombosis, such that the thrombin is reduced to a level enough to prevent thrombosis while the hemostatic function of the mechanism can be maintained with a sufficient level of thrombin remained (Schumacher, Luettgen et al., 2010, Arterioscler Thromb Vasc Biol, 30, 388-392).
Factor XIa can improve the production of blood clots and their stability in vitro. Factor XIa can increase production of thrombin during coagulation that is activated by a low level of tissue factor or thrombin. During coagulation activated by a higher level of tissue factor, the prothrombin time (TP) is not affected by the inhibition of factor XIa, whereas the activated partial thromboplastin time (aPTT) in the contact activation pathway is affected by the inhibition of factor XIa. Thus, inhibition of factor XIa can limit the amplification by thrombin resulting from the intrinsic cascade reaction, but has only a limited effect on the coagulation cascadereaction activated by tissue factor (von dem Borne, Cox et al., 2006, Blood Coagul Fibrinolysis, 17, 251-257).
In addition to affecting the production of thrombin, factor XI also plays a role in anti-fibrinolysis. The factor XI-dependent amplification by thrombin also leads to activation of the thrombin-activated plasmin inhibitor, and this inhibitor renders blood clots resistant to plasmin. That is, inhibition of factor XI may directly increase lysis of blood clots (Bouma, Marx et al., 2001, Thromb Res, 101, 329-354).
The potential of factor XI as a safe therapeutic target is convincingly demonstrated in hemophilia C patients. Factor XI-deficient hemophilia C patients have only a minor bleeding phenotype as compared to patients with hemophilia A (factor VIII deficiency) or hemophilia B (factor IX deficiency) (Gomez and Bolton-Maggs, 2008, Haemophilia, 14, 1183-1189; Duga and Salomon, 2009, Semin Thromb Hemost, 35, 416-425; Seligsohn, 2009, J Thromb Haemost, 7 Suppl 1, 84-87). Unlike hemophilia A or B, hemophilia C occurs in both genders. Patients with over 180 mutation types of haemophilia C have a low frequency of haemorrhage and rarely bleed spontaneously, and mild to moderate bleeding is more likely to occur in tissues particularly prone to fibrinolysis (such as the oral or urogenital system) generally after surgery or trauma. Although hemophilia C patients have an extended aPTT, the bleeding and coagulation levels are less related to each other. Severe factor XI deficiency can cause excessive bleeding in women during menstruation, but does not necessarily affect pregnancy and parturition of female patients. Bleeding associated with factor XI deficiency can be treated by the factor XI substitutive therapy with recombinant coagulation factors. Severe factor XI deficiency is usually a genetically inherited coagulation disorder, thus patients of this type are rare, and the phenotype is variable. In contrast, blood-coagulation factor V deficiency shows poor tolerability (Asselta and Peyvandi, 2009, Semin Thromb Hemost, 35, 382-389), and blood-coagulation factor X deficiency shows very serious phenotypes (Menegatti and Peyvandi, 2009, Semin Thromb Hemost, 35, 407-415).
Many findings on human and laboratory animals indicate that targeting factor XI/factor XIa may reduce the risk of certain thromboembolic diseases, and shows a much lower bleeding frequency as compared to the factors in the blood coagulation pathway that are currently targeted for an antithrombotic purpose (such as factor Xa, thrombin, etc.), despite the potential side effect of bleeding. Therefore, inhibiting factor XI may be now one of effective approaches to antithrombotic treatment of patients who may bleed.
Currently there are a limited number of candidate agents targeting factor XI, including factor XI antibodies, factor XI antisense nucleotides (ASOs), proteins or polypeptides, small chemical molecules, and a natural product isolated from sponges. Although factor XI ASOs are advantageous in that the deficiency of factor XIa caused by the ASOs therapy may be easily reversed by supplementing concentrated plasma-derived factor XIa (Zhang, Lowenberg et al., 2010, Blood, 116, 4684-4692), they take effect relatively slowly, and their antithrombotic effect is relatively weak. Small-molecule organic compounds have many advantages, such as good bioavailability upon oral administration and better patient compliance.
WO2013056034 describes novel substituted tetrahydroisoquinolines and derivatives thereof, as a blood-coagulation factor FXIa or plasma kallikrein inhibitor, is useful for treatment and prevention of thromboembolic diseases and has the following structural formula:
where A is a carbocycle; L is a linking group, such as a direct bond, alkyl, alkenyl, or alkynyl; and R1 to R5 are halogen, alkyl, alkoxy, and the like. It is not to be construed that the specific disclosure in this patent document is a part of the present invention.
WO2013055984 describes novel substituted tetrahydroisoquinolines and derivatives thereof, as a blood-coagulation factor FXIa or plasma kallikrein inhibitor, is useful for treatment and prevention of thromboembolic diseases and has the following structural formula:
where A is a carbocycle, B is a heterocycle, Q is C or N, L is a linking group such as a direct bond, alkyl, alkenyl or alkynyl, and R1 to R5 are halogen, alkyl, alkoxy, and the like. It is not to be construed that the specific disclosure in this patent document is a part of the present invention.
WO2013056060 describes novel substituted heterocyclic derivatives, as a blood-coagulation factor FXIa or plasma kallikrein inhibitor, is useful for treatment and prevention of thromboembolic diseases and has the following structural formula:
where A is a carbocycle, B is a heterocycle, L is a linking group such as a direct bond, alkyl, alkenyl or alkynyl, and R1 to R5 are halogen, alkyl, alkoxy, and the like. It is not to be construed that the specific disclosure in this patent document is a part of the present invention.
WO2013093484 describes pyrimidone or pyridone derivatives as a blood-coagulation factor FXIa inhibitor having the following structural formula, and use thereof for treatment and prevention of thromboembolic diseases:
where Cyc1, Cyc2 and Cyc3 are each a carbocycle or a heterocycle, and the substituents may be halogen, alkyl, alkoxy, and the like. It is not to be construed that the specific disclosure in this patent document is a part of the present invention.
WO2013118805 describes pyrrolidine derivatives as a blood-coagulation factor FXIa inhibitor having the following structural formula, and use thereof for treatment and prevention of thromboembolism and associated diseases:
where D and Q are each a carbocycle or a heterocycle, and the substituents may be halogen, alkyl, alkoxy, carbocycle, heterocycle and the like. It is not to be construed that the specific disclosure in this patent document is a part of the present invention.
The present invention aims to provide a novel bioactive compound as an inhibitor of blood-coagulation factor FXIa, which is useful for treatment of various diseases and complications caused by thrombosis, such as venous thrombosis, deep vein thrombosis, deep vein thrombosis of lower extremity, thrombophlebitis, cerebral arterial thrombosis, arterial embolism, coronary thrombosis, pulmonary embolism, cerebral embolism, renal embolism, hepatic vein thrombosis, portal vein thrombosis, chronic disseminated intravascular coagulation, limb and central microvascular arterial embolism, atherosclerosis, acute coronary syndrome, unstable angina, acute coronary arterial syndrome, myocardial infarction, arteriosclerosis, sudden ischemic death, transient ischemia, peripheral arterial occlusive disease, stroke, non-bacterial thrombotic endocarditis with arterial embolism, cerebrovascular disease and the like.